1-(2-methoxy-phenyl)-4-{8 2-(4-fluoro-benzamido)-ethyl{9 -piperazine

ABSTRACT

IN WHICH X represents one or more substituents selected from the group consisting of hydroxyl, nitro and halogen, R represents hydrogen, halogen, methyl, methoxy, or trifluoromethyl, and n is an integer from 2 to 5 inclusive, and their non-toxic salts, which are useful in therapy as analgesics; central nervious depressants, and tranquilizing agents.   The present invention provides novel substituted benzoic acid amides of the formula:

United States Patent [191 de Antoni et a1.

1 11 3,846,430 [451 Nov. 5, 1974 l-( 2-METHOXY-PHENYL)-4-[2-( 4-FLUORO- BENZAMIDO)-ETHYL]-PIPERAZINE [75] Inventors: Jacques de Antoni, Essonne;

Raymonde Eche, Paris, both of France [73] Assignee: Les Laboratories Bruneau et Cie,

Paris, France [22] Filed: July 31, 1972 [21] Appl. No.: 278,602

Related US. Application Data [30] Foreign Application Priority Data Jan. 12, 1968 France 68.135764 Apr. 11, 1968 France 68.147794 [52] US. Cl 260/268 PH, 260/268 CN, 424/250 [51] Int. Cl C07d 51/70 [58] Field of-seal'ch 260/268 PH [56] References Cited UNITED STATES PATENTS 2.722.529 11/1955 Fleming 260/268 PH 3,005,821 10/1961 Hayao 260/268 PH 3,274,194 9/1966 Hayuo 260/268 PH 3,488,352 l/1970 Schipper et a1... 260/268 PH 3,637,704 1/1972 Umsmoto 260/268 R 3,707,477 12/1972 Ost 260/268 PH 3,712,893 l/l973 Mauvernay et a1 260/268 PH FOREIGN PATENTS OR APPLICATIONS 1,543,944 9/1968 France 260/268 PH 1,537,901 8/1968 France 260/268 PH Primary ExaminerDonald G. Daus Attorney, Agent, or Firm-Stevens, Davis, Miller & Mosher [57] ABSTRACT The present invention provides novel substituted benzoic acid amides of the formula:

in which X represents one or more substituents selected from the group consisting of hydroxyl, nitro and halogen, R represents hydrogen, halogen, methyl,

methoxy, or trifluoromethyl, and n is an integer from 2 to 5 inclusive, and their non-toxic salts, which are useful in therapy as analgesics; central nervious depress ants, and tranquilizing agents.

1 Claim, N0 Drawings l 1-(2-METHOXY-PHENYL)-4-[2-G-FLUROR- BENZAMIDO)-ETHYL]-PIPERAZINE This is a continuation of application Ser. No. 888,087, filed 12-24-69 which is, in turn, a continuation in part of application Ser. No. 733,754, filed June 3, 1968, both now abandoned.

The present invention provides, as new compounds, the substituted benzoic acid amides of the formula:

in which n represents 2 or 3 and Y represents Cl or CF particularly the compound Cl l and their non-tonic salts with mineral or organic acids.

These new compounds are prepared by heating an ester of the formula:

it in which X is as hereinbefore defined and R, is alkyl of up to 3 carbon atoms or phenyl, with a compound of the formula:

Q-rv C:lH2nNH: R m m in which R and n are as hereinbefore defined.

The reaction may be carried out if desired in the presence of a catalyst such as an aluminium or alkali metal alcoholate, e.g. aluminium isopropoxide or sodium methoxide. The reaction can be carried out in the absence of a solvent using molten reactants, or in the presence of an inert solvant such as an aromatic hydrocarbon, for example xylene. When R, in formula 11 is a lower alkyl group, the corresponding alcohol may be distilled out of the reaction mixture as it is formed.

The compounds of formula 1 in which X represents nitro or halogen may also be prepared by reacting an acid chloride of the formula:

in which X is as hereinbefore defined, but is not hydroxyl, with a compound of formula III. The reaction may be carried out in the presence of an inert diluent such as chloroform or an aromatic hydrocarbon, or in a heterogeneous mixture in accordance with the Schotten-Baumann method.

The following Examples illustrate the invention.

EXAMPLE 1:

Method A Methyl salicylate (15.2 g.) or ethyl salicylate (16.6 g.) and 5-(4-phenyll -piperazinyl )-n-propy1amine (21.8 g.) are placed in a round-bottom flask and the mixture is heated to 200C. with agitation until no more alcohol is distilled off. This requires about 8 hours. The

mixture is cooled and dissolved in 25 ml. of isopropanol under reflux. After cooling, the crystalline product is filtered off and dried. The 3-(4-phenyl-l-piperazinyl) propylamide of salicylic acid is obtained, mp. 116C. lts hydrochloride, after recrystallisation from methanol, melts at 197C. Method B Phenyl salicylate (21.4 g-), 3-(4-pheny1-lpiperazinyl)-n-propylamine (21.8 g.) and pure xylene (20 ml.) are placed in a round-bottom flask and heated for 3 hours under reflux. The mixture is cooled, the xylene is removed by evaporation under reduced pressure, and the residue is recrystallised from isopropanol. 3-(4-phenyl-l-piperazinyl) propylamide of salicylic acid is obtained, m.p. 1 16C.

EXAMPLES 2-7 Following Method A or B Example 1, a (4-ary1-1- piperazinl)-a|kylamine is reacted with an ester of salicylic acid. The compounds obtained are set out in the following Table.

-Continued Example (4-phenyl-liperazim.p. (C) Salt, m.p. No. nyl)-alkylami ne recrystallisa- (C), re-

tion solvent crystallv sation solvent 6 3-[4-(3-methoxyphenyl)- 77 I hydrochlol-piperazinyll-nisopropanol ride 176, propylamine ethanol 7 3-[4-(3-chlorophenyl)- 105 hydrochlol-piperazinyH-nisopropanol ride 193, propylamine ethanol EXAMPLE 8; tallises out in suspension. After hours stirring at ambient temperature, the solid product is filtered off, (a) A mlxture of N'. plperazmeus washed with water and dried. After recrystallisation g.) 4-chlorobutyron1tr1le (10.4 g.), isopropanol (40 15 from ethanol (50 mm 4 [3 (4 fluorobenzamido) lg ml.) and anhydrous potassium carbonate (13.8 g.) are propylH phenylpiperazine is Obtained, mp 133C heatiad under rieflux agltatlon for w After The monohydrochloride is prepared by treating this coolmg the mlxtmie filtelied the gull/em ls evapo' base in solution in ethanol with the theoretical quantity rated and the reisldue .fracnonauy f l H of hydrogen chloride in solution in ethanol. It melts at fluorophenyl)-l-p1peraz1nyl]-n-butyron1tr1le 1S ob- 2O tained, b.p. 168172C./0.01 mm.I-1g., n 32 1.5380. Method B b) This nitrile (24.7 g.) in solution in ethanol (125 A solution of 3-(4-phenyl-l-piperazinyl)-nml.) saturated with ammonia is hydrogenated under a propylamine (21.9 g.) in chloroform (30 ml.) is added pressure of 80 kg./cm at a temperature of 100C. in slowly and with cooling to a solution of 4-fluorobenzoyl the presence of Raney nickel (1.5 ml.). When no more chloride (15.8 g.) in chloroform (50 ml.). The mixture hydrogen is absorbed, the pressure is released, the soluis allowed to stand for 15 hours at ambient temperature tion is filtered, the solvent is evaporated, and the resiand then stirred in the presence of 10 percent ammonia due is fractionally distilled. 4-[4-(4-fluorophenyl)-lsolution (40 ml. The organic phase is separated by depiperazinyl]-n-butylamine is obtained, b.p. cantation, washed with water, and dried over anhyl4ll45C./0.0l mm,I-1 1,5420. drous sodium sulphate. The chloroform is then distilled (c) Proceeding as in Examples 1 to 7, this substituted off under reduced pressure. The residue is recrystalbutylamine is converted into the 4-[4-(4- lised from ethanol (60 ml.), and the same product is fluorophenyl)-1-piperazinyll-n-butylamide of salicylic obtained as in Method A, m.p. 133C. acid. m.p. 156C. after recrystallisation from methanol. Method C.

The hydrochloride of this compound melts at Methyl-4-fluorobenzoate (15.4 g.), 3-(4-phenyl-l- 200202C. after recrystallisation from methanol. piperazinyl)-n-propylamine (21-9 g-). and xylene ml.) are placed in a round-bottom flask and heated EXAMPLES 9 & 10: under reflux until the methanol/xylene azeotrope no Proceeding as in Examples l-8, the following salilonger distills off, or for about 30 hours. The xylene is cylic acid amides are obtained: 40 then evaporated and the residue recrystallised from Examples (4-aryl-l-piperazinyl)- m.p. (C.), 7 Salt, m.p. (C.)

No. alkylamine recrystalrecrystalisalisation tion solvent solvent 9 3-[4-(4-fluorophenyU- 127 hydrochloride;

l-piperazinyll-n-proisopropanol 173-174"; pylamide ethanol l0 5-(4-phenyll -piper- 85 hydrochloride;

aziny )-n-pentylamide isopropanol 190-192;

ethanol EXAMPLE 11: ethanol. The same product is obtained as Methods A Method A and A solution of 4-fluorobenzoyl chloride (15.8 g.) m EXAMPLES 12 to benzene (30 ml.) is added to a mixture, cooled in ice,

of 3-(4-phenyl-l-piperazinyl)-n-propylamine (21.9 g.) Following Methods A, B or C of Example 11, a(4- in benzene (20 ml.) and a 20 percent solution of soaryl-Lpiperazinyl) alkylamine is reacted with abenzoic dium hydroxide (25 ml.) in the course of 45 minutes. acid chloride or ester, The compounds set out in the During the course of this addition a solid product crysfollowing Table are obtained.

Example (4-aryl-l-piperazinyl)- Benzoic acid chloride mp. (C.) recrystallisa- Monohydrochloride No. alkylamine or ester tion solvent m.p. C.) recrystallisation solvent 12 (4-phcnyl-l-piperazinyl)- 4-fluorobenzoic acid 175' 218-200". ethanol ethylamine ethanol 13 4-(4-phenyl-l-piperazinyl)- do. 233-235, ethanol n-butylamine ethanol -Continued Example (4-aryl-l-piperazinyl) Benzoic acid chloride mp. (C.) recrystallisa- Monohydrochloride No. alkylamine or ester tion solvent mp. (C.) recrystallisation solvent 14 4-[4-(4-fluorophenyl)-1- 148 piperazinyl]-n-butylamine 4-Flurorbenz'oic acid ethanol 226230 ethanol 15 3-(4-phenyl-l-piperazinyl)- 130 195-196 ethanol n-propylamine 4-chlorobenzoic acid isopropyl alcohol 16 do. 2-chlorobenz0ic acid 101 210-212, ethanol isopropyl alcohol 17 do. 2,4-dichlorobenzoic acid 94 172-173", ethanol isopropyl alcohol 18 do. 4-nitrobenzoic acid 1 16 189-191, ethanol ethanol EXAMPLE 19: 15 chloride (15.8 g.) in chloroform (50 ml.). The mixture is allowed to stand for 15 hours at ambient temperature Method A and then agitated in the presence of 10 percent ammo- A solution of 2-fluorobenzoyl chloride (15.8 g.) in

' phenyl-piperazine is obtained, m.p. 110l 11C.

The monohydrochloride is prepared by treating this base in solution in ethanol with an equivalent of hydrogen chloride in solution in ethanol. It melts at 194C. (dec.).

Method B A solution of 3-(4-phenil-l-piperazinyl)-npropylamine (21.9 g.) in chloroform ml.) is added slowly with cooling to a solution of 2-fluorobenzoyl nia solution ml. The organic phase is separated by decantation, washed with water, and dried over anhydrous sodium sulphate. The chloroform is then evaporated under reduced pressure and the residue recrystallised from ethanol ml.). The same product is obtained as in Method A, m.p. -111C. Method C A mixture of methyl 2-fluorobenzoate (15.4 g.), 3- (4-phenyl-1-piperazinyl)-n-propylamine (21.9 g.) and xylene 40 ml.) in a round-bottom flask is heated under reflux until methanol no longer distills off, or for about 30 hours. Xylene is then evaporated and the residue recrystallised from ethanol. The same product is obtained as in Methods A and B.

EXAMPLES 20 TO 49:

Following Method A, B or C of Example 19, a (4- aryl-l-piperazinyl) alkylamine is reacted with an appropriate benzoic acid chloride or ester. The products set out in the following Table are obtained.

Example (4-aryl-1-piperazinyl)- Benzoic acid chloride mp. (C) recrystalli- Monohydrochloride, m.p.

No. alkylamine or ester sation solvent (C), recrystallisation solvent 20 3-(4-phenyl-1-piperazinyl)- 3-fluorobenzoic acid l20l22, ethanol 16l(dec.). ethanol n-propylamine 21 do. 3-chlorobenzoic acid 1 1 1, isopropanol l68l69(de c.),

ethanol 22 2-(4-phenyl-l-piperazinyl)- 2-chlorobenzoic acid 126, ethanol 230, ethanol ethylamine 23 4-(4-phenyl-l-piperazinyldo. 1 19-120, 213-214 (dec.),

n-butylamine isopropanol isopropanol 24 2-(4-phenyll-1-piperaz1nyl)- 4-nitrobenzoic acid 174", propanol 216 (dec.),

et ylamine propanol 25 4-(4-pheriyl-l-piperazinyl)- do. 161, ethanol 233 (dec.), methanol n-butylamine 26 3-(4-phenyl-l-piperazinyl)- 3-nitrobenzoic acid 112, ethanol 216 (dec.), ethanol n-propylamine 27 do. Z-nitrobenzoic acid 112, ethanol 245 (dec.), ethanol 28 do. 2-chloro'4-nitrobenzoic 98, isopropyletheraci ethanol 157 (dec.), ethanol 29 2-[4-(4-fluorophenyD-l- 4-fluorobenzoic acid 164, ethanol 228-230 (dec.),

piperazinyl]ethylamine ethanol 30 3-[4-(4-fluorophen l)-1- 4-fluorobenzoic acid 144, isopropanol 178-180", isopropanol piperazinyll-n-propy amine 31 2-[4-(4-fluorophenyl)-l- 4-nitrobenzoic acid 152, methanol 215-216 (dec.),

piperazinyl]ethylamine ethanol 32 3-[4-(-4-fluorophen l)-ldo. -121", methanol 139 (dec.),

, piperazlnyll-n-propy amine ethanol 33 -[4-(4-fluoro henyl)-ldo. 139, methanol 190 (dec.),

piperazinyl1-nutylamine ethanol 34 3-[4-(3-chlorophen l)-1- 4-fluorobenzoic acid 100, isopropanol 207-210" (dec.),

. piperazinyll-n-propy amine isopropanol 35 do. 4-nitrobenzoic acid 109, ethanol 212-213 (dec.),

isopropanol 36 2-[4-(4-chlorophenyl)-1- 4-fluorobenzoic acid 176, ethanol 215-220 (dec.),

piperazinyl]ethylamine ethanol 37 do. 4-nitrobenzoic acid 162, ethanol 215 (dec.),

ethanol 38 3-[4-(4-chlorophen l)-1- 4-fluorobenzoic acid ethanol l86l88 (dec.),

piperazinyll-n-propy amine ethanol 39 do. 4-nitrobenzoic'acid 126, ethanol 223 (dec.)

ethanol -Continued lixumplc (4-aryll-pipe razinyl)- Benzoicacicl chloride m.p. (C) recrystalli- Monohydrochloride. m.p.

No. alkylamine or ester sation solvent I (C). recrystallisation solvent 40 3-[4-(4-methylphenyU-l- 4-fluorobenzoic acid 127-128, isopropanol 191-193 (dec.) iso- 'n l -nro lamine propano 41 -fi i -ni eihoii ypl ignylyldo. 134-135, isopropanol 234-240, isopropanol i erazin lleth lamine 42 p p do. y 4-nitrobenzoic acid 156, ethanol 229, methanol 43 2-[4 (4-methoxyphenyl)-l- 4-fluorobenzoic acid 163-165". ethanol 248-218 (dec.),

piperazinyllethylamine et ano o 44 3-[4-(4-methoxyphenyl)-l- O 196-498 (dec.).

piperazinyll-n-propylamine 4-fluorobenzoic acid 1 l7-1 1 8 tsopropanol isopgopanol 45 do. 4-nitrobenzoic acid 1 10, lsopropanol 190 (dec.

- isopropanol 1 46 2-[4-(3-trifluoromethyl- 4-fluorobenzoic acid 114-116", isopropanol 2l0-2l5. isopropanol phenyl)-l-piperazinyl] ethylamine a 47 do. 4-nitrobenzoic acid 1 18-1 19 3 isopropanol 189-190 isopropanol 48 3-[4-(3-trifluoromethyl- 4-fluorobenzoic acid 9293, isopropanol 178-180 isopropanol phenyl) l-piperazinyll-nro lamine o 49 p do. 4-nitrobenzoic acid 98-99", isopropanol 149-150 (dec.), isopropanol The amines used as starting materials in Examples 29, 31 and 47 can be prepared as follows:

A mixture of l-(p-fluorophenyl)piperazine (33.2 g.), chloroacetonitrile (14.7 g.), anhydrous potassium carbonate (26.9 g.) and methanol (150 ml.) is heated under reflux with agitation for 10 hours. The mixture is filtered hot and the solution saturated with ammonia at ambient temperature. The solution is then hydrogenated under a pressure of 80 kg/cm at 80-100C. for 2 hours in the presence of Raney nickel (4 ml.). After cooling and releasing the pressure, the Raney nickel is filtered off and the methanol evaporated. The residue is distilled at 0.05 mm.Hg. and 2-[4-(4-fluorophenyl)- l-piperazinyl]ethylamine is obtained, b.p. 138-142C/0.05 mm.l-lg, n 1.548.-

A mixture of 1-(m-trifluoromethylphenyl)piperazine (45.2 g.), chloroacetonitrile (14.7 g.), anhydrous potassium carbonate (26.9 g.) and methanol (150 ml.) is reacted and worked up as described in the last paragraph. 2-[4-(3-trifluoromethylphenyl)-1-piperazinyl1- ethylamine is obtained, b.p. 122125C/0.05 mm.l-lg, n,, 1.518.

EXAMPLE 50:

v benzene ml.) is added with stirring to a mixture,

cooled in ice, of 3-[4-(4-chloro-phenyl)-1- piperazinyl]-n-propylamine (25.4 g.) in benzene (20 ml.) and a 20 percent aqueous solution of sodium hydroxide (25 ml.) in the course of 45 minutes. The desired product appears in suspension in proportion to its being formed. After stirring for 15 hours at ambient temperature, thesolid product is filtered off, washed with water and dried. After recrystallisation from isochlorobenzamido)-1-propyl]-piperazine is obtained;

m.p. 118C.

The monohydrochloride is prepared by treating this base in solution in ethanol by the theoretical quantity of hydrogen chloride in solution in ethanol; m.p. 180C (dec.)

Method B A solution of 3-[4-(4-chlorophenyl)-l-piperazinyl]- n-propylamine (25.4 g.) in chloroform (50 ml.) is added slowly with cooling to a solution of 2- chlorobenzoyl chloride (17.5 g.) in chloroform (50 ml.). The mixture is allowed to stand for 15 hours at ambient temperature and then stirred in the presence of 10 percent ammonia aqueous solution (40 ml.). The organic phase is separated by decantation, washed with water and dried over sodium sulphate. The chloroform is then distilled off under reduced pressure. The residue is recrystallised from isopropanol; m.p. 118C. The same product is obtained as in Method A.

Method C Methyl 2-chlorobenzoate (17.1 g.), 3-[4-(4- chlorophenyl l -piperazinyl[-n-propylamine (25 .4 g.) and xylene (40 ml.) are placed in a round-bottom flask and heated under reflux until the methanol/xylene aze- I otrope no longer distills off, or for about 30 hours. The xylene is then evaporated and the residue recrystallised from isopropanol. The same product is obtained as in Methods A and B.

EXAMPLES 51 TO 54:

Following Methods A, B and C of Example 50, a-(4- aryl-l-piperazinyl)a1kylamine is heated with 2- chlorobenzoic acid chloride or ester. The compounds set out in the following Table are obtained from the specific (4-aryl-piperazino) alkylamines mentioned in propanol 1-(4-chlorophenyl)-4-[3-(2- the Table m.p. (C) Monohydrochloride Example (4-aryl-l-piperazirecrystallim.p. (C)

No. nyl)-alkylamine sation recrystallisasolvent tion solvant 51 2-[ 4-( B-trifluoromethylphenyl)-l-piperazinyl]- 145 196-200" ethylamine ethanol isopropanol S 2 3-1 4-( B-trifluoromethylphenyU-l-piperazinyll- -66 l72-l73 n-propylamine isopropylether isopropanol petroleum ether Pharmacological tests on the products of the Examples have given the following results. Acute Toxicity.

The LD 50 was calculated by the method of Karber & Behrens after intraperitoneal injection of the compounds into mice.

Compound of Example No. LD 50 (mg/kg.)

1 541 2 100 3 479 4 1,500 5 520 6 395 7 1,625 8 875 9 900 10 1.500 l l 138 12 1,275 13 271 I4 130 15 l 10 16 175 17 1 l6 18 93 19 158 20 137 21 80 22 I50 23 160 24 1,438 25 533 26 I38 27 258 28 194 29 238 30 138 3| 525 32 250 33 780 34 300 35 300 36 667 37 1.500 38 392 39 250 40 79 41 88 42 225 43 1,250 44 88 45 53 46 184 47 400 43 200 49 184 50 1.000 51 1.000 52 131 53 125 54 470 The symptoms observed are mainly central, torpor in low doses, excitomotor syndrome in high doses, palpebral ptosis.

ANALGESIC ACTIVITY The analgesic activity has been determined using the method of the heated plate (Eddy, J. PharmacoL, (1953) 107 p. 385) in a dose of 120 mg./kg. orally in mice. The temperature of the plate was 65C. and 10 to 20 mice were used in each test. The percentage increase in the reaction time (as measured by licking of the front paws) is measured as compared with the untreated controls.

Compound Dose %lncrease in reaction time at the end of Example MgJkg. of 6 hr. 1 hr 1% hr. 2 hrs.

l 7 22 54 15 2 16 36 44 47 3 I06 92 51 4 5 20 5 16 .5 31 5 7 0 6 40 43 7 I02 64 8 28 59 9 34 55 10 27 36 l l 120 265 0 50 21 1 18 25 94 0 12 120 0 0 50 0 l0 13 120 0 9 Compound of Dose Percentage increase in time of Example No. (mg/kg.) reaction after 1% hrs.

25 20 7 81 26 50 7 68 27 50 3.2 81 28 50 0 16 29 50 63 30 20 0 I6 31 50 0 0 32 0 0 33 120 100 254 34 50 73 79 35 50 41 87 36 50 79 57 37 50 265 I28 38 50 133 0 39 50 120 82 40 20 43 74 41 20 21 30 42 50 0 0 43 I20 77 46 44 20 27 65 45 10 32 40 46 50 66 47 50 26 61 48 50 210 92 49 50 0 '63 50 50 206 Continued I 1 COntinued Compound of Dose Percentage increase in time of Compound Number of mice Example No. (mg/kg.) reaction after of Example I lntraperitoneal which go to Mean duration 9% hr. 1% hrs. 5 No. I dose(mg./kg.) sleep again of second sleep 20 62 58 I 5 l 33 Z, is 15 15 7 6/8 I 29 minutes 52 50 12 I 47 1.5 4/8 25 minutes 53 gg g; g: 16 150 8/8 39 minutes 20 3 25 l 15 8/8 24-minutes 54 50 3 1.5 4/8 13 minutes 20 40 I 27 I7 I5 2/8 14 minutes 1.5 3/8 l3 minutes l8 l5 6/8 16 minutes CENTRAL DEPRESSANT ACTIVITY l5 1.5 3/ l5 mln e This was determined by measuring the ability of the 1 I5 I 8/8 21 minutes compounds to cause mice to go to sleep again who have been previously caused to go to sleep with sodiumhex- 20 7/8 minutes obarbital and have woken up. Groups of 8 mice receive 20 7/8 24 mmu'es an intravenous injection of sodiumhexobarbital in a 2| 15 7/8 18 minutes dose of 56 mg./kg. When each mouse awakes, it is in- 15 5/3 mmules ected lntrapentoneally w1th the compound under test 22 15 6/8 9 minutes and the mouse 1s observed to see 1f 1t goes to sleep again, and, if it does, the duration of sleep is measured. 23 i 5 f2 In every case, the criterion for sleep is the loss of the 24 150 8/8 35 minutes fighting reflex. l5 5/8 14 minutes 25 150 8/8 50 minutes l5 5/8 20minutes Compound Number of mice of Example lnlraperitoncal which go to Mean duration 26 8/8 mlnules No. dose(mg./kg.) sleep again of second sleep l9 mlnutes 27 I5 7/8 32 minutes I W2 l.5 8/8 13 minutes 9 i l 5 5/8 28 15 7/8 18 minutes 2 5 8/8 I 5 minutes L5 5/8 11 mlnutes 3/8 I 6 29 15 8/8 1 50 minutes 3 200 8/8 32 minutes 1 15 6/8 29 minutes 30 15 7/8 41 mlnutes 16 0 1.5 1/8 10 minutes 9 l 4 i 31 150 8/8 50 minutes 8 i I I5 8/8 2l minutes I 5 4/ I 1 es l.5 4/8 ll minutes 5 i2 i2 32 15 7/8 50 minutes 5 3 1 minutes L5 7/8 15 minutes 6 4 minutes 33 150 8/8 75 minutes 5 4 3 3 minutes 15 8/8 15 minutes 7 L5 7/8 13 minutes 7 I50 7 8/8 26 minutes I 2 8 1 t 34 150 7/8 mlnutes 15 mm es 50 l5 5/8 13 minutes 8 I50 8/8 61 minutes I l5 8/8 25 minutes 35 150 /8 65 mmutes l.5 5/8 l3 minutes I 5 6/8 1 l minutes 9 I50 8/8 more than 4 min. 6 1 I50 7/8 37 minutes l5 5/8 l6 minutes 5 1 4/8 13 mmutes 1.5 3/8 11 minutes 5 5 37 150 6/8 22 m1nutes I0 I50 8/8 37 minutes 15 6/8 12 minutes l5 5/8 16 minutes I 1.5 3/8 6 minutes 38 0 8/8 30 mmutes l5 6/8 13 minutes 1] 15 8/8 38 minutes 1.5- 8/8 28 minutes 60 39 150 7/8 30 m1nutes v 15 3/8 7 minutes 12 150 8/8 33 minutes 1 15 7/8 26 minutes 40 15 6/8 20 minutes l.5 3/8 18 minutes 41 15 7/8 26 minutes 13 150 8/8 32 minutes 1.5 6/8 19 minutes l5 7/8 18 minutes 6 1.5 3/8 11 minutes 5 42 150 8/8 minutes l5 6/8 17 minutes 14 v 50 8/8 41 minutes 15 5/8 18 minutes 43 l50 8/8 38 minutes 1.5 2/8 3 minutes 15 7/8 25 minutes -Continued Compound Number of mice of Example lntraperitoneal which go to Mean duration No. dose(mg./kg.) sleep again of second sleep 44 15 5/8 25 minutes 45 15 /8 minute 46 15 6/8 19 minutes 47 150 4/8 20 minutes 15 1/8 2 minutes 48 150 8/8 51 minutes 15 4/8 15 minutes 49 15 3/8 10 minutes 50 15 7/8 '21 minutes 1.5 3/8 12 minutes 51 15 3/8 11 minutes 52 15 8/8 22 minutes 1.5 4/8 11 minutes 53 15 6/8 20 minutes 1.5 3/8 9 minutes 54 15 3/8 13 minutes Hydrochloride of the amide of Example 1 0.10 g.

starch 0.0975 g.

magnesium stearate 0.025 g A suppository may be made up asfollows:

Hydrochloride of the amide of Example 1 0.150 g.

semi-synthetic glyceride q.s.p. which will give a suppository of 1.50 g.

Asagents. for potentiating the effect of barbituric hypnotics, the compounds defined above can be used either alone or in association with barbiturates in the form of tablets, capsules or suppositories. A suitable formulation for a tablet is as follows:

Hydrochloride of the amide of Example 1 0.05 g. secobarbital 0.05 g. starch 0.0975 g. magnesium stearate 0.025 g.

A suitable formulation for a suppository is as follows:

Hydrochloride of the amide of Example 1 0.05 g. secobarbital 0.100 g. semi-synthetic glyceride q.s.p to give a suppository weighing 1.50 g.

The compounds of the invention can be used in medicaments as the bases or as their salts with non-toxic mineral 'and orgariic acids, especially hydrochloric acid. The compositions can be in a form suitable for oral, endorectal or parenteral administration, and in particular as tablets, pills or capsules containing 100 mg. of active substance, as suppositories containing 250 mg. of active substance, or as ampoules containing mg. of active substance. The dosage is generally from 10 to 1,000 mg. per day by oral administration in the case of an adult.

ANTIHISTAMINIC EFFECT The antihistarninic effect of the compounds of Examples 19 to 49 has been determined on the isolated guinea pig ileum in aerated Tyrodes solution at 37C. For each compound, theED 50 (in ug/ml. of Tyrode solution) is determined. The results obtained are given in the following table.

Compound of Example No. ED 50 27 0.75 r I 28 0.06 29 0.125 30 0.011 31 0.04 32 0.0065 33 0.004 34 0.004 35 0.003 36 0.10 37 0.13 38 0.010 39 0.005 40 0.010 41 0.30 42 0.15 43 0.80 44 0.15 45 0.05 46 0.12 47 0.025 48 0.020 49 0.015 50 a 0.25 51 2 0.25 52 2 0.25 53 a 0.25 54 2 0.25

It has further been found that the compound of the formula where R,, R R and R have the significances tabu lated below Example No. R R; m R; 7 R

24 H N 2 H H 1 l d F 3 d i d 42 Cl N0 2 CH O (1 33 (1 d 4 d F 41 (1 F 2 cu o u 23 Cl H 4 H1 d" exhibit valuable antitussive properties, the preferred compounds in this respect being those of Examples 24, 33, 23 and 41. The compounds may be in a form suitable for oral, endorectal or local administration, for instance as tablets, pills, capsules, suppositories, syrups, potions, collutories or aerosols. For example, the compound of Example 24 may be administered as capsules containing 20 mg. thereof, the daily dosage generally ranging from 40 to 100 mg. in the case of an adult.

It has also been found that the compounds of the formula where R,, R R and n have the significances tabulated below Example No. R R R; n

33 NO, H F 4 3! NO, H F 2 46 F F,C H 2 29 F H l- 2 47 NO, MC H '2 4) N0, I"; C H 3 13 F H H 4 exhibit valuable anti-inflammatory properties, the preferred compounds in this respect being those of Exam- Percentage of re- Example No. Dose mg./kg.

(p.o.) duction of oedema Phenylbutazone 60 51 (control) 30 42 We claim:

I. The substituted benzoic acid amide which is l-(2- methoxy-phenyl )-4-[ 2-( 4-fl uoro-benzamido )-ethyl piperazine. 

1. THE SUBSTITUTED BENZONIC ACID AMIDE WHICH IS 1-(2METHOXY-PHENYL)-4-(2-(4-FUORO-BENZAMIDO)-ETHYL)PIPERAZINE. 